Modified release dosage forms

ABSTRACT

A dosage form comprises: (a) a core comprising at least one active ingredient; and (b) a molded shell which surrounds the core, wherein the shell provides a predetermined time delay of greater than one hour for the onset of dissolution of the active ingredient upon contacting of the dosage form with a liquid medium and the delay is independent of the pH of the liquid medium. The weight of the shell may be at least 50 percent of the weight of the core, and the shell may have a thickness of about 500-4000 microns, or be substantially free of pores having a diameter of 0.5 to 5 microns.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to modified release dosage forms such asmodified release pharmaceutical compositions. More particularly, thisinvention relates to modified release dosage forms having a corecontaining at least one active ingredient and a shell surrounding thecore, in which the shell provides a delay of greater than one hour forthe onset of dissolution of the active ingredient upon contacting of thedosage form with a liquid medium such as water or gastrointestinalfluids, and the delay is independent of the pH of the liquid medium.

[0003] 2. Background Information

[0004] Modified release pharmaceutical dosage forms have long been usedto optimize drug delivery and enhance patient compliance, especially byreducing the number of doses of medicine the patient must take in a day.For this purpose, it is often desirable to modify the rate of release ofa drug (one particularly preferred type of active ingredient) from adosage form into the gastro-intestinal (g.i.) fluids of a patient,especially to slow the release in order to provide prolonged action ofthe drug in the body.

[0005] The rate at which an orally delivered pharmaceutical activeingredient reaches its site of action in the body depends on a number offactors, including the rate and extent of drug absorption through thegastro-intestinal (g.i.) mucosa. To be absorbed into the circulatorysystem (blood), the drug must first be dissolved in the g.i. fluids. Formany drugs, diffusion across the g.i. membranes is relatively rapidcompared to dissolution. In these cases, the dissolution of the activeingredient is the rate limiting step in drug absorption, and controllingthe rate of dissolution allows the formulator to control the rate ofdrug absorption into the circulatory system of a patient.

[0006] An important objective of modified release dosage forms is toprovide a desired blood concentration versus time (pharmacokinetic, orPK) profile for the drug. Fundamentally, the PK profile for a drug isgoverned by the rate of absorption of the drug into the blood, and therate of elimination of the drug from the blood. The type of PK profiledesired depends, among other factors, on the particular activeingredient, and physiological condition being treated.

[0007] One desirable PK profile for a number of drugs and conditions, isachieved by a dosage form that delivers a delayed release dissolutionprofile, in which the release of drug from the dosage form is delayedfor a pre-determined time after ingestion by the patient. The delayperiod (“lag time”) can be followed either by prompt release of theactive ingredient (“delayed burst”), or by sustained (prolonged,extended, or retarded) release of the active ingredient (“delayed thensustained”).

[0008] A particularly desirable type of delayed release PK profile is a“pulsatile” profile, in which for example, a first dose is deliveredimmediately, followed by a delay corresponding approximately to the timeduring which a therapeutic concentration of the first dose is maintainedin the blood, followed by either prompt or sustained release of asubsequent dose of the same drug.

[0009] A particularly challenging aspect of the design of delayedrelease systems involves the predictability and repeatability of the lagtime in vivo. Physiological systems, e.g. the human g.i. tract, have ahigh degree of inter- and intra-subject variability, for example inintestinal motility and pH. For the purpose of repeatability andpredictability, it is desirable to have a delayed release mechanism thatis independent of the pH of the environment in which the dosage formmust release drug.

[0010] Well known mechanisms by which a dosage form (or drug deliverysystem) can deliver drug at a modified rate (e.g. delayed, pulsatile,sustained, prolonged, extended or retarded release) include diffusion,erosion, and osmosis.

[0011] One classic diffusion-controlled release system comprises activeingredient, distributed throughout an insoluble porous matrix throughwhich the active ingredient must diffuse in order to be absorbed intothe bloodstream of the patient. The amount of drug release (M) at agiven time at sink conditions (i.e. drug concentration at the matrixsurface is much greater than drug concentration in the bulk solution)depends on the area (A) of the matrix, the diffusion coefficient (D),the porosity (E) and tortuosity (T) of the matrix, the drug solubility(Cs) in the dissolution medium, time (t) and the drug concentration (Cp)in the dosage form:

M=A(DE/T(2Cp−ECs)(Cs)t)^(1/2)

[0012] It will be noted in the above relationship that the amount ofdrug released is generally proportional to the square root of time.Assuming factors such as matrix porosity and tortuosity are constantwithin the dosage form, a plot of amount of drug released versus thesquare root of time should be linear.

[0013] A commonly used erosion-controlled release system comprises a“matrix” throughout which the drug is distributed. The matrix typicallycomprises a material which swells at the surface, and slowly dissolvesaway layer by layer, liberating drug as it dissolves. The rate of drugrelease, dM/dt, in these systems depends on the rate of erosion (dx/dt)of the matrix, the concentration profile in the matrix, and the surfacearea (A) of the system:

dM/dt=A{dx/dt}{f(C)}

[0014] Again, variation in one or more terms, such as surface area,typically lead to a non-constant release rate of drug. In general, therate of drug release from erosion-controlled release systems typicallyfollows first order kinetics.

[0015] Another type of erosion controlled delivery system utilizesmaterials which swell and dissolve slowly by surface erosion areadditionally useful for providing a delayed release of pharmaceuticalactive ingredient. Delayed release is useful, for example in pulsatileor repeat action delivery systems, in which an immediate release dose isdelivered, followed by a pre-determined lag time before a subsequentdose is delivered from the system. In these systems, the lag time (T₁)depends on the thickness (h) of the erodible layer, and the rate oferosion (dx/dt) of the matrix, which in turn depends on the swellingrate and solubility of the matrix components:

T ₁ =h(dx/dt)

[0016] The cumulative amount of drug (M) released from these systems ata given time generally follows the equation:

M=(dM/dt)(t−T ₁)

[0017] where dM/dt is generally described by either thediffusion-controlled or erosion-controlled equations above, and T₁ isthe lag time.

[0018] It is often practical to design dosage forms that use acombination of the above mechanisms to achieve a particularly desirablerelease profile for a particular active ingredient.

[0019] Current delayed-release systems are limited by the availablemethods for manufacturing them, as well as the materials that aresuitable for use with the current methods. A shell, or coating, whichconfers modified release properties, is typically applied viaconventional methods, such as for example, spray-coating in a coatingpan. Pan-coating produces a single shell which essentially surrounds thecore. The single shell is inherently limited in its functionality. It ispossible via pan-coating to apply multiple concentric shells, each witha different functionality, however such systems are limited in that theouter shell must first dissolve before the functionality conferred byeach successive layer can be realized. Additionally, the coatingcompositions that can be applied via spraying are limited by theirviscosity. Spray-coating methods suffer the further limitations of beingtime-intensive and costly. One well-known and commonly used design forproviding delayed release of a drug employs an enteric coating material,either on particles containing the drug or on the surface of a dosageform. Enteric materials are generally selected from polymer systemswhich are soluble only in fluid environments with a certain pH range,higher than that of typical gastric fluid, for example pH greater than5.5, greater than pH 6.0, or greater than pH 7.0. While these systemsmay be useful for protecting certain acid-labile active ingredients fromgastric fluids, or for protecting the stomach lining from damage bycertain active ingredients, they are limited in their applicability toprogrammed time-delay systems due to variability in gastrointestinal pHand motility.

[0020] The pH-independent delay of drug release has been achieved byconventional spray-coating methods. For example, G. Maffione et al.,“High-Viscosity HPMC as a Film-Coating Agent,” Drug Development andIndustrial Pharmacy (1993) 19(16), pp. 2043-2053, describes a core ortablet matrix, surrounded by a shell or coating, which provides adelayed burst dissolution profile. Coating levels were 12.5-25% of theweight of the core. A preferred coating formula employs a swellablefilm-former dispersed in non-aqueous solvent. Low polymer concentrations(5-10%), and the use of ethanol as a “non-solvent” were required forsprayability.

[0021] It is also known, via pan coating, to deliver a first dose ofactive ingredient from a coating, and a second dose of active ingredientfrom a core. U.S. Pat. No. 4,576,604, for example, discloses an osmoticdevice (dosage form) comprising a drug compartment surrounded by a wall(coating) in which the coating may comprise an immediate release dose ofdrug, and the inner drug compartment may comprise a sustained releasedose of drug.

[0022] Alternately, conventional controlled release systems may beprepared by compression, to produce either multiple stacked layers, orcore and shell configurations. Modified release dosage forms preparedvia compression are exemplified in U.S. Pat. Nos. 5,738,874 and6,294,200, and WO 99/51209.

[0023] It is possible via compression-coating to produce apH-independent time delayed drug release. U.S. Pat. No. 5,464,633discloses delayed-release dosage forms in which an external coatinglayer was applied by a compression coating process. The coating levelranged from 105 percent to 140 percent of the weight of the core inorder to yield product with the desired time delayed profile.

[0024] Compression-coated dosage forms are limited by the shellthickness and shell composition. Gunsel et al., “Compression-coated andlayer tablets” in Pharmaceutical Dosage Forms—Tablets, edited by H. A.Lieberman, L. Lachman, and J. B. Schwartz, (2nd ed., rev. and expandedMarcel Dekker) Inc., p. 247-284, for example, discloses the thickness ofcompression coated shells is typically between 800 and 1200 microns.

[0025] It is one object of this invention to provide a dosage formhaving a core which contains at least one active ingredient and a shellsurrounding the core, in which the shell has a weight of at least 50percent of the weight of the core, the shell provides a delay of greaterthan one hour for the onset of dissolution of the active ingredient uponcontacting of the dosage form with a liquid medium, and the delay isindependent of the pH of the liquid medium. Other objects, features andadvantages of this invention will be apparent to those skilled in theart from the following detailed description of the invention.

SUMMARY OF THE INVENTION

[0026] The dosage form of this invention comprises:

[0027] (a) a core comprising at least one active ingredient; and

[0028] (b) a molded shell which surrounds the core, wherein the shellprovides a predetermined time delay of greater than one hour for theonset of dissolution of the active ingredient upon contacting of thedosage form with a liquid medium and the delay is independent of the pHof the liquid medium.

[0029] In one embodiment, the weight of the shell is at least 50 percentof the weight of the core.

[0030] In another embodiment, the shell has a thickness from about 500to about 4000 microns.

[0031] In another embodiment, the shell has a thickness from about 100to 600 microns.

[0032] In another embodiment, the shell has a surface gloss of at leastabout 150 gloss units.

[0033] In another embodiment, the shell is substantially free of poreshaving a diameter of 0.5 to 5.0 microns.

[0034] In another embodiment, the shell comprises at least 30% of athermal reversible carrier.

[0035] In another embodiment, the shell comprises at least about 10% ofa film-former.

[0036] In another embodiment, the shell additionally comprises at leastone active ingredient which may be the same or different than the activeingredient contained in the core.

[0037] In another embodiment, the dosage form additionally comprises anouter coating which covers at least a portion of the shell, and theouter coating comprises at least one active ingredient which may be thesame or different than the active ingredient contained in the core.

[0038] In another embodiment, the core is a compressed tablet.

[0039] In another embodiment, the core comprises coated particles of atleast one active ingredient.

[0040] In another embodiment, the core is made by molding.

[0041] In another embodiment, the core is substantially free of poreshaving a diameter of 0.5 to 5.0 microns.

[0042] In another embodiment, the core comprises at least about 30weight percent of a thermal-reversible carrier.

[0043] In another embodiment, the core comprises a release-modifyingexcipient.

[0044] In another embodiment, the shell is not a compression coatingapplied to the core.

[0045] In another embodiment, the dosage form provides an immediaterelease of at least one active ingredient, followed by a delay of atleast about 1 hour, followed by a burst release of at least one activeingredient.

[0046] In another embodiment, the shell is prepared using a solvent-freemolding process.

[0047] In another embodiment, the shell comprises at least 30% by weightof a thermal-reversible carrier.

[0048] In another embodiment, the shell comprises up to 55% by weight ofa swellable, erodible hydrophilic material.

[0049] In another embodiment, the shell is prepared using asolvent-based molding process.

[0050] In another embodiment, the shell comprises at least 10% by weightof a film-former.

[0051] In another embodiment, the shell comprises up to 55% by weight ofa release-modifying excipient.

[0052] In another embodiment, the dosage form provides a delayed burstrelease profile of the active ingredient.

[0053] In another embodiment, the dosage form provides a delayed andsustained release profile of the active ingredient.

[0054] In another embodiment, the dosage form provides a pulsatilerelease profile of the active ingredient.

[0055] In another embodiment, the core or portion thereof furthercomprises shellac at a level of about 5 to about 15 weight percent ofthe core or portion thereof.

[0056] In another embodiment, the shell or portion thereof furthercomprises shellac at a level of about 5 to about 15 weight percent ofthe shell or portion thereof.

[0057] In another embodiment, the thermal reversible carrier is selectedfrom the group consisting of polyethylene glycol, polyethylene oxide andcopolymers and combinations thereof.

[0058] In another embodiment, the film former is polyethylene oxide.

[0059] In another embodiment, the release-modifying excipient is aswelling cross-linked polymer.

[0060] In another embodiment, the swelling cross-linked polymer iscroscarmellose sodium.

[0061] In another embodiment, the shell further comprises a plasticizer.

[0062] In another embodiment, the plasticizer is tributyl citrate.

[0063] In another embodiment, the shell is prepared using asolvent-based molding process, and the weight of the shell is from about10 percent to about 60 percent of the weight of the core.

BRIEF DESCRIPTION OF THE DRAWINGS

[0064]FIG. 1 depicts a cross-sectional view of one embodiment of thisinvention.

[0065]FIG. 2 depicts the percent release of active ingredient vs. hoursfor the dosage form of Example 1.

[0066]FIG. 3 depicts the percent release of active ingredient vs. hoursfor the dosage form of Example 2.

[0067]FIG. 4 depicts the percent release of active ingredient vs. hoursfor the dosage form of Example 3.

DETAILED DESCRIPTION OF THE INVENTION

[0068] As used herein, the term “dosage form” applies to any solidobject, semi-solid, or liquid composition designed to contain a specificpre-determined amount (i.e. dose) of a certain ingredient, for examplean active ingredient as defined below. Suitable dosage forms may bepharmaceutical drug delivery systems, including those for oraladministration, buccal administration, rectal administration, topical ormucosal delivery, or subcutaneous implants, or other implanted drugdelivery systems; or compositions for delivering minerals, vitamins andother nutraceuticals, oral care agents, flavorants, and the like.Preferably the dosage forms of the present invention are considered tobe solid, however they may contain liquid or semi-solid components. In aparticularly preferred embodiment, the dosage form is an orallyadministered system for delivering a pharmaceutical active ingredient tothe gastro-intestinal tract of a human.

[0069] The active ingredient employed in the dosage forms of thisinvention may be found within the core, the shell or a combinationthereof. Suitable active ingredients for use in this invention includefor example pharmaceuticals, minerals, vitamins and othernutraceuticals, oral care agents, flavorants and mixtures thereof.Suitable pharmaceuticals include analgesics, anti-inflammatory agents,antiarthritics, anesthetics, antihistamines, antitussives, antibiotics,anti-infective agents, antivirals, anticoagulants, antidepressants,antidiabetic agents, antiemetics, antiflatulents, antifungals,antispasmodics, appetite suppressants, bronchodilators, cardiovascularagents, central nervous system agents, central nervous systemstimulants, decongestants, diuretics, expectorants, gastrointestinalagents, migraine preparations, motion sickness products, mucolytics,muscle relaxants, osteoporosis preparations, oral contraceptives,polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tractagents and mixtures thereof.

[0070] Suitable oral care agents include breath fresheners, toothwhiteners, antimicrobial agents, tooth mineralizers, tooth decayinhibitors, topical anesthetics, mucoprotectants, and the like.

[0071] Suitable flavorants include menthol, peppermint, mint flavors,fruit flavors, chocolate, vanilla, bubblegum flavors, coffee flavors,liqueur flavors and combinations and the like.

[0072] Examples of suitable gastrointestinal agents include antacidssuch as calcium carbonate, magnesium hydroxide, magnesium oxide,magnesium carbonate, aluminum hydroxide, sodium bicarbonate,dihydroxyaluminum sodium carbonate; stimulant laxatives, such asbisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe,castor oil, ricinoleic acid, and dehydrocholic acid, and mixturesthereof; H2 receptor antagonists, such as famotadine, ranitidine,cimetadine, nizatidine; proton pump inhibitors such as omeprazole orlansoprazole; gastrointestinal cytoprotectives, such as sucraflate andmisoprostol; gastrointestinal prokinetics, such as prucalopride,antibiotics for H. pylori, such as clarithromycin, amoxicillin,tetracycline, and metronidazole; antidiarrheals, such as diphenoxylateand loperamide; glycopyrrolate; antiemetics, such as ondansetron,analgesics, such as mesalamine.

[0073] In one embodiment of the invention, the active ingredient may beselected from bisacodyl, famotadine, ranitidine, cimetidine,prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth,antacids, and pharmaceutically acceptable salts, esters, isomers, andmixtures thereof.

[0074] In another embodiment, the active ingredient is selected fromanalgesics, anti-inflammatories, and antipyretics, e.g. non-steroidalanti-inflammatory drugs (NSAIDs), including propionic acid derivatives,e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acidderivatives, e.g. indomethacin, diclofenac, sulindac, tolmetin, and thelike; fenamic acid derivatives, e.g. mefanamic acid, meclofenamic acid,flufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g.diflunisal, flufenisal, and the like; and oxicams, e.g. piroxicam,sudoxicam, isoxicam, meloxicam, and the like. In a particularlypreferred embodiment, the active ingredient is selected from propionicacid derivative NSAID, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen,fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen,oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts,derivatives, and combinations thereof. In a particular embodiment of theinvention, the active ingredient may be selected from acetaminophen,acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen,diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, andpharmaceutically acceptable salts, esters, isomers, and mixturesthereof.

[0075] In another embodiment of the invention, the active ingredient maybe selected from pseudoephedrine, phenylpropanolamine, chlorpheniramine,dextromethorphan, diphenhydramine, astemizole, terfenadine,fexofenadine, loratadine, desloratadine, cetirizine, mixtures thereofand pharmaceutically acceptable salts, esters, isomers, and mixturesthereof.

[0076] Examples of suitable polydimethylsiloxanes, which include, butare not limited to dimethicone and simethicone, are those disclosed inU.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of eachis expressly incorporated herein by reference. As used herein, the term“simethicone” refers to the broader class of polydimethylsiloxanes,including but not limited to simethicone and dimethicone.

[0077] The active ingredient or ingredients are present in the dosageform in a therapeutically effective amount, which is an amount thatproduces the desired therapeutic response upon oral administration andcan be readily determined by one skilled in the art. In determining suchamounts, the particular active ingredient being administered, thebioavailability characteristics of the active ingredient, the doseregime, the age and weight of the patient, and other factors must beconsidered, as known in the art. Typically, the dosage form comprises atleast about 5 weight percent, preferably, the dosage form comprises atleast about 20 weight percent of the active ingredient. In one preferredembodiment, the core comprises at least about 25 weight percent (basedon the weight of the core) of the active ingredient.

[0078] The active ingredient or ingredients may be present in the dosageform in any form. For example, the active ingredient may be dispersed atthe molecular level, e.g. melted or dissolved, within the dosage form,or may be in the form of particles, which in turn may be coated oruncoated. If the active ingredient is in form of particles, theparticles (whether coated or uncoated) typically have an averageparticle size of about 1-2000 microns. In one preferred embodiment, suchparticles are crystals having an average particle size of about 1-300microns. In another preferred embodiment, the particles are granules orpellets having an average particle size of about 50-2000 microns,preferably about 50-1000 microns, most preferably about 100-800 microns.

[0079] In certain embodiments of the invention, at least a portion ofthe active ingredient may be coated with a release-modifying coating, asknown in the art. This advantageously provides an additional tool foroptimizing the release profile of the active ingredient from the dosageform Examples of suitable release modifying coatings are described inU.S. Pat. Nos. 4,173,626; 4,863,742; 4,980,170; 4,984,240;5,286,497,5,912,013; 6,270,805; and 6,322,819. Commercially available modifiedrelease coated active particles may also be employed. Accordingly, allor a portion of one or more active ingredients may be coated with arelease-modifying material.

[0080] In certain other embodiments of the invention, a further degreeof flexibility in designing the dosage forms of the present inventioncan be achieved through the use of an additional outer coatingoverlaying the shell. The additional outer coating may be applied byknown methods, for example by spraying, dipping, printing, rollercoating, compression, or by molding. In such embodiments, the dosageform of the invention comprises a core containing at least one activeingredient; a molded shell which surrounds the core, wherein the shellprovides a predetermined time delay of greater than one hour for theonset of dissolution of the active ingredient upon contacting of thedosage form with a liquid medium and the delay is independent of the pHof the liquid medium; and an outer coating which covers at least aportion of the shell. In one particularly preferred embodiment, thedosage form is a pulsatile drug delivery system, in which the outercoating comprises an active ingredient, which is released immediately(i.e. the dissolution of the active ingredient from the outer coatingconforms to USP specifications for immediate release dosage forms of theparticular active ingredient employed).

[0081] In embodiments in which it is desired for the active ingredientto be absorbed into the systemic circulation of an animal, the activeingredient or ingredients are preferably capable of dissolution uponcontact with a fluid such as water, stomach acid, intestinal fluid orthe like. In one embodiment, the dissolution characteristics of at leastone active ingredient meets USP specifications for immediate releasetablets containing the active ingredient. For example, for acetaminophentablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USPapparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophencontained in the dosage form is released therefrom within 30 minutesafter dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least80% of the ibuprofen contained in the dosage form is released therefromwithin 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856(1999). In embodiments in which at least one active ingredient isreleased immediately, the immediately released active ingredient ispreferrably contained in the shell or on the surface of the shell, e.g.in a further coating residing upon at least a portion of the shell. Inanother embodiment, the dissolution characteristics of at least oneactive ingredient are modified: e.g. controlled, sustained, extended,retarded, prolonged, delayed and the like. In embodiments in which atleast one active ingredient is released in a modified manner, themodified release active ingredient is preferably contained in the core.

[0082]FIG. 1 depicts a cross-sectional view of one embodiment of thisinvention. In FIG. 1, a core 2 comprises an active ingredient. The core2 is surrounded by a shell 4 which provides a delay of greater than onehour to the onset of dissolution of the active ingredient uponcontacting of the dosage form with a liquid medium. The delay of theonset of dissolution is independent of the pH of the liquid medium. Theweight of the shell material is at least 50 percent of the weight of thecore material.

[0083] The core of the present invention may be prepared by any suitablemethod, including for example compression, or molding, and depending onthe method by which it is made, typically comprises active ingredientand a variety of excipients (inactive ingredients which may be usefulfor conferring desired physical properties to the core).

[0084] In one embodiment, the core is prepared by the compressionmethods and apparatus described in copending U.S. patent applicationSer. No. 09/966,509, pages 16-27, the disclosure of which isincorporated herein by reference. Specifically, the core is made using arotary compression module comprising a fill zone, insertion zone,compression zone, ejection zone, and purge zone in a single apparatushaving a double row die construction as shown in FIG. 6 of U.S. patentapplication Ser. No. 09/966,509. The dies of the compression module arepreferably filled using the assistance of a vacuum, with filters locatedin or near each die. The purge zone of the compression module includesan optional powder recovery system to recover excess powder from thefilters and return the powder to the dies.

[0085] In embodiments in which the core or a portion thereof is made bycompression, suitable excipients include fillers, binders,disintegrants, lubricants, glidants, and the like, as known in the art.In embodiments in which the core is made by compression and additionallyconfers modified release of an active ingredient contained therein, thecore preferably further comprises a release-modifying excipient forcompression.

[0086] Suitable fillers for use in making the core, or a portionthereof, by compression include water-soluble compressible carbohydratessuch as sugars, which include dextrose, sucrose, maltose, and lactose,sugar-alcohols, which include mannitol, sorbitol, maltitol, xylitol,starch hydrolysates, which include dextrins, and maltodextrins, and thelike, water insoluble plasticly deforming materials such asmicrocrystalline cellulose or other cellulosic derivatives,water-insoluble brittle fracture materials such as dicalcium phosphate,tricalcium phosphate and the like and mixtures thereof.

[0087] Suitable binders for making the core, or a portion thereof, bycompression include dry binders such as polyvinyl pyrrolidone,hydroxypropylmethylcellulose, and the like; wet binders such aswater-soluble polymers, including hydrocolloids such as alginates, agar,guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth,pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan,laminarin, scleroglucan, gum arabic, inulin, pectin, whelan, rhamsan,zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinylpyrrolidone, cellulosics, starches, and the like; and derivatives andmixtures thereof.

[0088] Suitable disintegrants for making the core, or a portion thereof,by compression include sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches,microcrystalline cellulose, and the like.

[0089] Suitable lubricants for making the core, or a portion thereof, bycompression include long chain fatty acids and their salts, such asmagnesium stearate and stearic acid, talc, and waxes.

[0090] Suitable glidants for making the core, or a portion thereof, bycompression include colloidal silicon dioxide, and the like.

[0091] Suitable release-modifying excipients for making the core, or aportion thereof, by compression include swellable erodible hydrophilicmaterials, insoluble edible materials, pH-dependent polymers, and thelike.

[0092] Suitable swellable erodible hydrophilic materials for use asrelease-modifying excipients for making the core, or a portion thereof,by compression, include water swellable cellulose derivatives,polyalkalene glycols, thermoplastic polyalkalene oxides, acrylicpolymers, hydrocolloids, clays, gelling starches, and swellingcross-linked polymers, and derivitives, copolymers, and combinationsthereof. Examples of suitable water swellable cellulose derivativesinclude sodium carboxymethylcellulose, cross-linkedhydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC) such as those available from DowChemical Company under the tradename METHOCEL K4M, METHOCEL K15M, andMETHOCEL K100M, hydroxyisopropylcellulose,hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples ofsuitable polyalkalene glyclols include polyethylene glycol. Examples ofsuitable thermoplastic polyalkalene oxides include poly (ethyleneoxide). Examples of suitable acrylic polymers include potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL(high-molceular weight cross-linked acrylic acid homopolymers andcopolymers), and the like. Examples of suitable hydrocolloids includealginates, agar, guar gum, locust bean gum, kappa carrageenan, iotacarrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellangum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan,chitin, cyclodextrin, chitosan. Examples of suitable clays includesmectites such as bentonite, kaolin, and laponite; magnesiumtrisilicate, magnesium aluminum silicate, and the like, and derivativesand mixtures thereof. Examples of suitable gelling starches include acidhydrolyzed starches, swelling starches such as sodium starch glycolate,and derivatives thereof. Examples of suitable swelling cross-linkedpolymers include cross-linked polyvinyl pyrrolidone, cross-linked agar,and cross-linked carboxymethylcellose sodium.

[0093] Suitable insoluble edible materials for use as release-modifyingexcipients for making the core, or a portion thereof, by compressioninclude water-insoluble polymers, and low-melting hydrophobic materials.Examples of suitable water-insoluble polymers include ethylcellulose,polyvinyl alcohols, polyvinyl acetate, polycaprolactones, celluloseacetate and its derivatives, acrylates, methacrylates, acrylic acidcopolymers; and the like and derivatives, copolymers, and combinationsthereof. Suitable low-melting hydrophobic materials include fats, fattyacid esters, phospholipids, and waxes. Examples of suitable fats includehydrogenated vegetable oils such as for example cocoa butter,hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil; and free fatty acids andtheir salts. Examples of suitable fatty acid esters include sucrosefatty acid esters, mono, di, and triglycerides, glyceryl behenate,glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate,glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroylmacrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples ofsuitable phospholipids include phosphotidyl choline, phosphotidylserene, phosphotidyl enositol, and phosphotidic acid. Examples ofsuitable waxes include carnauba wax, spermaceti wax, beeswax, candelillawax, shellac wax, microcrystalline wax, and paraffin wax; fat-containingmixtures such as chocolate; and the like.

[0094] Suitable pH-dependent polymers for use as release-modifyingexcipients for making the core, or a portion thereof, by compressioninclude enteric cellulose derivatives, for example hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, cellulose acetate phthalate; natural resins such as shellacand zein; enteric acetate derivatives such as for examplepolyvinylacetate phthalate, cellulose acetate phthalate, acetaldehydedimethylcellulose acetate; and enteric acrylate derivatives such as forexample polymethacrylate-based polymers such as poly(methacrylic acid,methyl methacrylate) 1:2, which is commercially available from RohmPharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid,methyl methacrylate) 1:1, which is commercially available from RohmPharma GmbH under the tradename EUDRAGIT L and the like, andderivatives, salts, copolymers, and combinations thereof.

[0095] Suitable pharmaceutically acceptable adjuvants for making thecore, or a portion thereof, by compression include, preservatives; highintensity sweeteners such as aspartame, acesulfame potassium, sucralose,and saccharin; flavorants; colorants; antioxidants; surfactants; wettingagents; and the like and mixtures thereof.

[0096] In certain preferred embodiments of the invention, the core, orthe shell, or a portion thereof, is prepared by molding. In suchembodiments, the core, or the shell, or a portion thereof, is made froma flowable material. The flowable material may be any edible materialthat is flowable at a temperature between about 37° C. and 250° C., andthat is solid, semi-solid, or can form a gel at a temperature betweenabout −10° C. and about 80° C., e.g. between about −10° C. and about 55°C., or between about −10° C. and about 35° C. When it is in the fluid orflowable state, the flowable material may comprise a dissolved or moltencomponent, and optionally a solvent such as for example water or organicsolvents, or combinations thereof. The solvent may be partially orsubstantially removed by drying.

[0097] Suitable flowable materials for making the core, or the shell, ora portion thereof by molding include those comprising thermoplasticmaterials; film formers; thickeners such as gelling polymers orhydrocolloids; low melting hydrophobic materials; non-crystallizablecarbohydrates; and the like. Suitable molten components of the flowablematerial include thermoplastic materials, low melting hydrophobicmaterials, and the like. Suitable dissolved components for the flowablematerial include film formers, thickeners such as gelling polymers orhydrocolloids, non-crystallizable carbohydrates, and the like.

[0098] Suitable thermoplastic materials for use as components of theflowable material for making the core or the shell or a portion thereofby molding can be molded and shaped when heated, and include both watersoluble and water insoluble polymers that are generally linear, notcrosslinked, nor strongly hydrogen bonded to adjacent polymer chains.Examples of suitable thermoplastic materials include thermoplastic waterswellable cellulose derivatives, thermoplastic water insoluble cellulosederivatrives, thermoplastic vinyl polymers, thermoplastic starches,thermplastic polyalkalene glycols, thermoplastic polyalkalene oxides,and amorphous sugar-glass, and the like, and derivatives, copolymers,and combinations thereof. Examples of suitable thermoplastic waterswellable cellulose derivatives include hydroxypropyl cellulose (HPC),hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC). Examples ofsuitable thermoplastic water insoluble cellulose derivatrives includecellulose acetate (CA), ethyl cellulose (EC), cellulose acetate butyrate(CAB), cellulose propionate. Examples of suitable thermoplastic vinylpolymers include, polyvinyl alcohol, polyvinyl acetate (PVA) andpolyvinyl pyrrolidone (PVP). Examples of suitable thermoplastic starchesare disclosed for example in U.S. Pat. No. 5,427,614, which isincorporated herein by reference. Examples of suitable thermoplasticpolyalkalene glycols include polyethylene glycol; Examples of suitablethermoplastic polyalkalene oxides include polyethylene oxide having amolecular weight from about 100,000 to about 900,000 Daltons. Othersuitable thermoplastic materials include sugar in the form on anamorphous glass such as that used to make hard candy forms.

[0099] Any film former known in the art is suitable for use in theflowable material of the present invention. Examples of suitable filmformers include, but are not limited to, film-forming water solublepolymers, film-forming proteins, film-forming water insoluble polymers,and film-forming pH-dependent polymers. Suitable film-forming watersoluble polymers include water soluble vinyl polymers such aspolyvinylalcohol, polyvinylacetate (PVA); water solublepolycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch,pullulan, methylethyl starch, carboxymethyl starch, pre-gelatinizedstarches, and film-forming modified starches; water swellable cellulosederivatives such as hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose (MC), hydroxyethylmethylcellulose(HEMC), hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose(HEEC), and hydroxyethylhydroxypropylmethyl cellulose (HEMPMC); watersoluble copolymers such as methacrylic acid and methacrylate estercopolymers, polyvinyl alcohol and polyethylene glycol copolymers,polyethylene oxide and polyvinylpyrrolidone copolymers; and derivativesand combinations thereof. Suitable film-forming proteins may be naturalor chemically modified, and include gelatin, whey protein, myofibrillarproteins, coaggulatable proteins such as albumin, casein, caseinates andcasein isolates, soy protein and soy protein isolates, zein; andpolymers, derivatives and mixtures thereof. Suitable film-forming waterinsoluble polymers, include for example ethylcellulose, polyvinylalcohols, polyvinyl acetate, polycaprolactones, cellulose acetate andits derivatives, acrylates, methacrylates, acrylic acid copolymers; andthe like and derivatives, copolymers, and combinations thereof. Suitablefilm-forming pH-dependent polymers include enteric cellulosederivatives, such as for example hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate succinate, celluloseacetate phthalate; natural resins such as shellac and zein; entericacetate derivatives such as for example polyvinylacetate phthalate,cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; andenteric acrylate derivatives such as for example polymethacrylate-basedpolymers such as poly(methacrylic acid, methyl methacrylate) 1:2, whichis commercially available from Rohm Pharma GmbH under the tradenameEUDRAGIT S and poly(methacrylic acid, methyl methacrylate) 1:1, which iscommercially available from Rohm Pharma GmbH under the tradenameEUDRAGIT L and the like, and derivatives, salts, copolymers, andcombinations thereof.

[0100] One suitable hydroxypropylmethylcellulose compound for use as athermoplastic film-forming water soluble polymer is “HPMC 2910”, whichis a cellulose ether having a degree of substitution of about 1.9 and ahydroxypropyl molar substitution of 0.23, and containing, based upon thetotal weight of the compound, from about 29% to about 30% methoxylgroups and from about 7% to about 12% hydroxylpropyl groups. HPMC 2910is commercially available from the Dow Chemical Company under thetradename METHOCEL E. METHOCEL E5, which is one grade of HPMC-2910suitable for use in the present invention, has a viscosity of about 4 to6 cps (4 to 6 millipascal-seconds) at 20° C. in a 2% aqueous solution asdetermined by a Ubbelohde viscometer. Similarly, METHOCEL E6, which isanother grade of HPMC-2910 suitable for use in the present invention,has a viscosity of about 5 to 7 cps (5 to 7 millipascal-seconds) at 20°C. in a 2% aqueous solution as determined by a Ubbelohde viscometer.METHOCEL E15, which is another grade of HPMC-2910 suitable for use inthe present invention, has a viscosity of about 15000 cps (15millipascal-seconds) at 20° C. in a 2% aqueous solution as determined bya Ubbelohde viscometer. As used herein, “degree of substitution” shallmean the average number of substituent groups attached to aanhydroglucose ring, and “hydroxypropyl molar substitution” shall meanthe number of moles of hydroxypropyl per mole anhydroglucose.

[0101] One suitable polyvinyl alcohol and polyethylene glycol copolymeris commercially available from BASF Corporation under the tradenameKOLLICOAT IR.

[0102] As used herein, “modified starches” include starches that havebeen modified by crosslinking, chemically modified for improvedstability or optimized performance, or physically modified for improvedsolubility properties or optimized performance. Examples ofchemically-modified starches are well known in the art and typicallyinclude those starches that have been chemically treated to causereplacement of some of its hydroxyl groups with either ester or ethergroups. Crosslinking, as used herein, may occur in modified starcheswhen two hydroxyl groups on neighboring starch molecules are chemicallylinked. As used herein, “pre-gelatinized starches” or “instantizedstarches” refers to modified starches that have been pre-wetted, thendried to enhance their cold-water solubility. Suitable modified starchesare commercially available from several suppliers such as, for example,A. E. Staley Manufacturing Company, and National Starch & ChemicalCompany. One suitable film forming modified starch includes thepre-gelatinized waxy maize derivative starches that are commerciallyavailable from National Starch & Chemical Company under the tradenamesPURITY GUM and FILMSET, and derivatives, copolymers, and mixturesthereof. Such waxy maize starches typically contain, based upon thetotal weight of the starch, from about 0 percent to about 18 percent ofamylose and from about 100% to about 88% of amylopectin.

[0103] Another suitable film forming modified starch includes thehydroxypropylated starches, in which some of the hydroxyl groups of thestarch have been etherified with hydroxypropyl groups, usually viatreatment with propylene oxide. One example of a suitable hydroxypropylstarch that possesses film-forming properties is available from GrainProcessing Company under the tradename, PURE-COTE B790.

[0104] Suitable tapioca dextrins for use as film formers include thoseavailable from National Starch & Chemical Company under the tradenamesCRYSTAL GUM or K-4484, and derivatives thereof such as modified foodstarch derived from tapioca, which is available from National Starch andChemical under the tradename PURITY GUM 40, and copolymers and mixturesthereof.

[0105] Any thickener known in the art is suitable for use in theflowable material. Examples of such thickeners include but are notlimited to hydrocolloids (also referred to herein as gelling polymers),clays, gelling starches, and crystallizable carbohydrates, andderivatives, copolymers and mixtures thereof. Examples of suitablehydrocolloids (also referred to herein as gelling polymers) such asalginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic,tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan,pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, whelan,rhamsan, zooglan, methyl an, chitin, cyclodextrin, chitosan. Examples ofsuitable clays include smectites such as bentonite, kaolin, andlaponite; magnesium trisilicate, magnesium aluminum silicate, and thelike, and derivatives and mixtures thereof. Examples of suitable gellingstarches include acid hydrolyzed starches, and derivatives and mixturesthereof. Additional suitable thickening hydrocolloids includelow-moisture polymer solutions such as mixtures of gelatin and otherhydrocolloids at water contents up to about 30%, such as for examplethose used to make “gummi” confection forms. Suitable crystallizablecarbohydrates include the monosaccharides and the oligosaccharides. Ofthe monosaccharides, the aldohexoses e.g., the D and L isomers ofallose, altrose, glucose, mannose, gulose, idose, galactose, talose, andthe ketohexoses e.g., the D and L isomers of fructose and sorbose alongwith their hydrogenated analogs: e.g., glucitol (sorbitol), and mannitolare preferred. Of the oligosaccharides, the 1,2-disaccharides sucroseand trehalose, the 1,4-disaccharides maltose, lactose, and cellobiose,and the 1,6-disaccharides gentiobiose and melibiose, as well as thetrisaccharide raffinose are preferred along with the isomerized form ofsucrose known as isomaltulose and its hydrogenated analog isomalt. Otherhydrogenated forms of reducing disaccharides (such as maltose andlactose), for example, maltitol and lactitol are also preferred.Additionally, the hydrogenated forms of the aldopentoses: e.g., D and Lribose, arabinose, xylose, and lyxose and the hydrogenated forms of thealdotetroses: e.g., D and L erythrose and threose are preferred and areexemplified by xylitol and erythritol, respectively.

[0106] In one embodiment of the invention, the flowable materialcomprises gelatin as a gelling polymer. Gelatin is a natural,thermogelling polymer. It is a tasteless and colorless mixture ofderived proteins of the albuminous class which is ordinarily soluble inwarm water. Two types of gelatin—Type A and Type B—are commonly used.Type A gelatin is a derivative of acid-treated raw materials. Type Bgelatin is a derivative of alkali-treated raw materials. The moisturecontent of gelatin, as well as its Bloom strength, composition andoriginal gelatin processing conditions, determine its transitiontemperature between liquid and solid. Bloom is a standard measure of thestrength of a gelatin gel, and is roughly correlated with molecularweight. Bloom is defined as the weight in grams required to move ahalf-inch diameter plastic plunger 4 mm into a 6.67% gelatin gel thathas been held at 10° C. for 17 hours. In a preferred embodiment, theflowable material is an aqueous solution comprising 20% 275 Bloom porkskin gelatin, 20% 250 Bloom Bone Gelatin, and approximately 60% water.

[0107] Suitable xanthan gums include those available from C. P. KelcoCompany under the tradenames KELTROL 1000, XANTROL 180, or K9B310.

[0108] “Acid-hydrolyzed starch,” as used herein, is one type of modifiedstarch that results from treating a starch suspension with dilute acidat a temperature below the gelatinization point of the starch. Duringthe acid hydrolysis, the granular form of the starch is maintained inthe starch suspension, and the hydrolysis reaction is ended byneutralization, filtration and drying once the desired degree ofhydrolysis is reached. As a result, the average molecular size of thestarch polymers is reduced. Acid-hydrolyzed starches (also known as“thin boiling starches”) tend to have a much lower hot viscosity thanthe same native starch as well as a strong tendency to gel when cooled.

[0109] “Gelling starches,” as used herein, include those starches that,when combined with water and heated to a temperature sufficient to forma solution, thereafter form a gel upon cooling to a temperature belowthe gelation point of the starch. Examples of gelling starches include,but are not limited to, acid hydrolyzed starches such as that availablefrom Grain Processing Corporation under the tradename PURE-SET B950;hydroxypropyl distarch phosphate such as that available from GrainProcessing Corporation under the tradename, PURE-GEL B990, and mixturesthereof.

[0110] Suitable low-melting hydrophobic materials for use as componentsof the flowable material for making the core, or the shell, or a portionthereof by molding include fats, fatty acid esters, phospholipids, andwaxes. Examples of suitable fats include hydrogenated vegetable oilssuch as for example cocoa butter, hydrogenated palm kernel oil,hydrogenated cottonseed oil, hydrogenated sunflower oil, andhydrogenated soybean oil; and free fatty acids and their salts. Examplesof suitable fatty acid esters include sucrose fatty acid esters, mono,di, and triglycerides, glyceryl behenate, glyceryl palmitostearate,glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, andstearoyl macrogol-32 glycerides. Examples of suitable phospholipidsinclude phosphotidyl choline, phosphotidyl serene, phosphotidylenositol, and phosphotidic acid. Examples of suitable waxes includecamauba wax, spernaceti wax, beeswax, candelilla wax, shellac wax,microcrystalline wax, and paraffin wax; fat-containing mixtures such aschocolate; and the like.

[0111] Suitable non-crystallizable carbohydrates for use as componentsof the flowable material for making the core, or the shell, or a portionthereof by molding include non-crystallizable sugars such aspolydextrose, and starch hydrolysates, e.g. glucose syrup, corn syrup,and high fructose corn syrup; and non-crystallizable sugar-alcohols suchas maltitol syrup.

[0112] Suitable solvents for optional use as components of the flowablematerial for making the core, or the shell, or a portion thereof bymolding include water; polar organic solvents such as methanol, ethanol,isopropanol, acetone, and the like; and non-polar organic solvents suchas methylene chloride, and the like; and mixtures thereof.

[0113] The flowable material for making the core or the shell or aportion thereof by molding may optionally comprise adjuvants orexcipients, which may comprise up to about 30% by weight of the flowablematerial. Examples of suitable adjuvants or excipients includeplasticizers, detackifiers, humectants, surfactants, anti-foamingagents, colorants, flavorants, sweeteners, opacifiers, and the like.Suitable plasticizers for making the core, the shell, or a portionthereof, by molding include, but not be limited to polyethylene glycol;propylene glycol; glycerin; sorbitol; triethyl citrate; tribuyl citrate;dibutyl sebecate; vegetable oils such as castor oil, rape oil, oliveoil, and sesame oil; surfactants such as polysorbates, sodium laurylsulfates, and dioctyl-sodium sulfosuccinates; mono acetate of glycerol;diacetate of glycerol; triacetate of glycerol; natural gums; triacetin;acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate;diethylmalonate; dioctylphthalate; dibutylsuccinate;glyceroltributyrate; hydrogenated castor oil; fatty acids; substitutedtriglycerides and glycerides; and the like and/or mixtures thereof. Incertain embodiments, the shell is substantially free of plasticizers,i.e. contains less than about 1%, say less than about 0.01% ofplasticizers.

[0114] In one preferred embodiment, the flowable material comprises lessthan 5% humectants, or alternately is substantially free of humectants,such as glycerin, sorbitol, maltitol, xylitol, or propylene glycol.Humectants have traditionally been included in pre-formed films employedin enrobing processes, such as that disclosed in U.S. Pat. Nos.5,146,730 and 5,459,983, assigned to Banner Gelatin Products Corp., inorder to ensure adequate flexibility or plasticity and bondability ofthe film during processing. Humectants function by binding water andretaining it in the film. Pre-formed films used in enrobing processescan typically comprise up to 45% water. Disadvantageously, the presenceof humectant prolongs the drying process, and can adversely affect thestability of the finished dosage form.

[0115] In one embodiment of the invention, the core, the shell, or aportion thereof is made by the thermal setting molding method andapparatus described in copending U.S. patent application Ser. No.09/966,450, pages 57-63, the disclosure of which is incorporated hereinby reference. In this embodiment, the core, the shell, or a portionthereof is formed by injecting a starting material in flowable form intoa molding chamber. The starting material preferably comprises an activeingredient and a thermal setting material at a temperature above themelting point of the thermal setting material but below thedecomposition temperature of the active ingredient. The startingmaterial is cooled and solidifies in the molding chamber into a shapedform (i.e., having the shape of the mold).

[0116] According to this method, the starting material must be inflowable form. For example, it may comprise solid particles suspended ina molten matrix, for example a polymer matrix. The starting material maybe completely molten or in the form of a paste. The starting materialmay comprise an active ingredient dissolved in a molten material.Alternatively, the starting material may be made by dissolving a solidin a solvent, which solvent is then evaporated from the startingmaterial after it has been molded.

[0117] The starting material may comprise any edible material which isdesirable to incorporate into a shaped form, including activeingredients, nutritionals, vitamins, minerals, flavors, sweeteners, andthe like. Preferably, the starting material comprises an activeingredient and a thermal setting material. The thermal setting materialmay be any edible material that is flowable at a temperature betweenabout 37 and about 120° C., and that is a solid at a temperature betweenabout 0 and about 35° C. Preferred thermal setting materials includewater-soluble polymers such as polyalkylene glycols, polyethylene oxidesand derivatives, and sucrose esters; fats such as cocoa butter,hydrogenated vegetable oil such as palm kernel oil, cottonseed oil,sunflower oil, and soybean oil; mono-, di-, and triglycerides,phospholipids, waxes such as carnuba wax, spermaceti wax, beeswax,candelilla wax, shellac wax, microcrystalline wax, and paraffin wax;fat-containing mixtures such as chocolate; sugar in the form on anamorphous glass such as that used to make hard candy forms, sugar in asupersaturated solution such as that used to make fondant forms;low-moisture polymer solutions such as mixtures of gelatin and otherhydrocolloids at water contents up to about 30% such as those used tomake “gummi” confection forms. In a particularly preferred embodiment,the thermal setting material is a water-soluble polymer such aspolyethylene glycol.

[0118] In another embodiment of the invention, the core, the shell, or aportion thereof is make using the thermal cycle molding method andapparatus described in copending U.S. patent application Ser. No.09/966,497, pages 27-51, the disclosure of which is also incorporatedherein by reference. In the thermal cycle molding method and apparatusof U.S. patent application Ser. No. 09/966,497, a thermal cycle moldingmodule having the general configuration shown in FIG. 3 therein isemployed. The thermal cycle molding module 200 comprises a rotor 202around which a plurality of mold units 204 are disposed. The thermalcycle molding module includes a reservoir 206 (see FIG. 4) for holdingflowable material to make the core. In addition, the thermal cyclemolding module is provided with a temperature control system for rapidlyheating and cooling the mold units. FIGS. 55 and 56 depict such atemperature control system 600.

[0119] In certain embodiments the core or portions thereof may be moldedusing a solvent-free process. In such embodiments, the core may compriseactive ingredient contained within an excipient matrix. The matrixtypically comprises at least about 30 percent, e.g. at least about 45weight percent of a thermal-reversible carrier, and optionally up toabout 30 weight percent of various adjuvants such as for exampleplasticizers, gelling agents, strengthening agents, colorants,stabilizers, preservatives, and the like as known in the art. The matrixmay optionally further comprise up to about 55 weight percent of one ormore release-modifying moldable excipients as described below.

[0120] The core may be in a variety of different shapes. For example,the core may be shaped as a polyhedron, such as a cube, pyramid, prism,or the like; or may have the geometry of a space figure with somenon-flat faces, such as a cone, truncated cone, cylinder, sphere, torus,or the like. In cetrain embodiments, the core has one or more majorfaces. For example in embodiments wherein the core is a compressedtablet, the core surface typically has two opposing major faces formedby contact with the upper and lower punch faces in the compressionmachine. In such embodiments the core surface typically furthercomprises a “belly-band” located between the two major faces, and formedby contact with the die walls in the compression machine. Exemplary coreshapes which may be employed include tablet shapes formed fromcompression tooling shapes described by “The Elizabeth Companies TabletDesign Training Manual,” (Elizabeth Carbide Die Co., Inc., p.7(McKeesport, Pa.) (incorporated herein by reference) as follows (thetablet shape corresponds inversely to the shape of the compressiontooling):

[0121] 1. Shallow Concave.

[0122] 2. Standard Concave.

[0123] 3. Deep Concave.

[0124] 4. Extra Deep Concave.

[0125] 5. Modified Ball Concave.

[0126] 6. Standard Concave Bisect.

[0127] 7. Standard Concave Double Bisect.

[0128] 8. Standard Concave European Bisect.

[0129] 9. Standard Concave Partial Bisect.

[0130] 10. Double Radius.

[0131] 11. Bevel & Concave.

[0132] 12. Flat Plain.

[0133] 13. Flat-Faced-Beveled Edge (F.F.B.E.).

[0134] 14. F.F.B.E. Bisect.

[0135] 15. F.F.B.E. Double Bisect.

[0136] 16. Ring.

[0137] 17. Dimple.

[0138] 18. Ellipse.

[0139] 19. Oval.

[0140] 20. Capsule.

[0141] 21. Rectangle.

[0142] 22. Square.

[0143] 23. Triangle.

[0144] 24. Hexagon.

[0145] 25. Pentagon.

[0146] 26. Octagon.

[0147] 27. Diamond.

[0148] 28. Arrowhead.

[0149] 29. Bullet.

[0150] 30. Barrel.

[0151] 31. Half Moon.

[0152] 32. Shield.

[0153] 33. Heart.

[0154] 34. Almond.

[0155] 35. House/Home Plate.

[0156] 36. Parallelogram.

[0157] 37. Trapezoid.

[0158] 38. FIG. 8/Bar Bell.

[0159] 39. Bow Tie.

[0160] 40. Uneven Triangle.

[0161] In one embodiment of the invention, the core comprises multipleportions, for example a first portion and a second portion. The portionsmay be prepared by the same or different methods and mated using varioustechniques, such as thermal cycle molding and thermal setting moldingmethods described herein. For example, the first and second portions mayboth be made by compression, or both may be made by molding. Or oneportion may be made by compression and the other by molding. The same ordifferent active ingredient may be present in the first and secondportions of the core. Alternately, one or more core portions may besubstantially free of active ingredients.

[0162] In certain embodiments of the invention, the core or a portionthereof may function to confer modified release properties to at leastone active ingredient contained therein. In such embodiments, whereinthe core or core portion is made by compression, as previously noted,the core preferably comprises a release-modifying excipient forcompression. In such embodiments, wherein the core or core portion ismade by molding, as previously noted, the core preferably comprises arelease-modifying moldable excipient.

[0163] In embodiments in which the core or a portion thereof functionsas an eroding matrix from which dispersed active ingredient is liberatedin a sustained, extended, prolonged, or retarded manner, the coreportion preferably comprises a release-modifying compressible ormoldable excipient selected from swellable erodible hydrophilicmaterials, pH-dependent polymers, and combinations thereof.

[0164] In embodiments in which the core or a portion thereof functionsas a diffusional matrix through which active ingredient is liberated ina sustained, extended, prolonged, or retarded manner, the core portionpreferably comprises a release-modifying excipient selected fromcombinations of insoluble edible materials and pore-formers.Alternately, in such embodiments in which the core portion is preparedby molding, the thermal-reversible carrier may function by dissolvingand forming pores or channels through which the active ingredient may beliberated.

[0165] The shell of the present invention may be prepared by molding,using a solvent-free process, or a solvent-based process, and dependingon the method by which it is made, typically comprises a variety ofexcipients which are useful for conferring desired properties to theshell. The shell may optionally further comprise one or more activeingredients.

[0166] In embodiments in which the shell is prepared using asolvent-free molding process, the shell will typically comprise at leastabout 30 percent, e.g. at least about 45 percent by weight of athermal-reversible carrier. The shell may optionally further comprise upto about 55 weight percent of a release modifying excipient. The shellmay optionally further comprise up to about 30 weight percent total ofvarious plasticizers, adjuvants and excipients. In certain embodimentsin which the shell is prepared by solvent-free molding, the releasemodifying excipient is preferrably selected from swellable, erodiblehydrophilic materials.

[0167] In embodiments in which the shell is prepared using asolvent-based molding process, the shell will typically comprise atleast about 10 weight percent, e.g. at least about 12 weight percent orat least about 15 weight percent or at least about 20 weight percent orat least about 25 weight percent of a film-former. Here, thesolvent-molded shell may optionally further comprise up to about 55weight percent of a release-modifying excipient. The solvent-moldedshell portions may again also optionally further comprise up to about 30weight percent total of various plasticizers, adjuvants, and excipients.

[0168] Suitable thermal-reversible carriers for making the core, or theshell, or a portion thereof, by solvent-free molding are thermoplasticmaterials typically having a melting point below about 11° C., morepreferably between about 20 and about 100° C. Examples of suitablethermal-reversible carriers for solvent-free molding includethermplastic polyalkalene glycols, thermoplastic polyalkalene oxides,low melting hydrophobic materials, thermoplastic polymers, thermoplasticstarches, and the like. Suitable thermoplastic polyalkylene glycols foruse as thermal-reversible carriers include polyethylene glycol havingmolecular weight from about 100 to about 20,000, e.g. from about 100 toabout 8,000, say from about 1000 to about 8,000 Daltons. Suitablethermoplastic polyalkalene oxides include polyethylene oxide having amolecular weight from about 100,000 to about 900,000 Daltons. Suitablelow-melting hydrophobic materials for use as thermal-reversible carriersinclude fats, fatty acid esters, phospholipids, and waxes which aresolid at room temperature, fat-containing mixtures such as chocolate;and the like. Examples of suitable fats include hydrogenated vegetableoils such as for example cocoa butter, hydrogenated palm kernel oil,hydrogenated cottonseed oil, hydrogenated sunflower oil, andhydrogenated soybean oil; and free fatty acids and their salts. Examplesof suitable fatty acid esters include sucrose fatty acid esters, mono,di, and triglycerides, glyceryl behenate, glyceryl palmitostearate,glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, andstearoyl macrogol-32 glycerides. Examples of suitable phospholipidsinclude phosphotidyl choline, phosphotidyl serene, phosphotidylenositol, and phosphotidic acid. Examples of suitable waxes that aresolid at room temperature include camauba wax, spermaceti wax, beeswax,candelilla wax, shellac wax, microcrystalline wax, and paraffin wax.Suitable thermoplastic polymers for use as thermal-reversible carriersinclude thermoplastic water swellable cellulose derivatives,thermoplastic water insoluble polymers, thermoplastic vinyl polymers.Suitable thermoplastic water swellable cellulose derivatives includeinclude hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC),carboxymethylcellulose (CMC), cross-linked hydroxypropylcellulose,hydroxypropyl cellulose (HPC), hydroxybutylcellulose (HBC),hydroxyethylcellulose (HEC), hydroxypropylethylcellulose,hydroxypropylbutylcellulose, hydroxypropylethylcellulose, and salts,derivatives, copolymers, and combinations thereof. Suitablethermoplastic water insoluble polymers include ethylcellulose, polyvinylalcohols, polyvinyl acetate, polycaprolactones, cellulose acetate andits derivatives, acrylates, methacrylates, acrylic acid copolymers, andthe like and derivatives, copolymers, and combinations thereof. Suitablethermoplastic vinyl polymers include polyvinylacetate, polyvinylalcohol, and polyvinyl pyrrolidone (PVP). Examples of suitablethermoplastic starches for use as thermal-reversible carriers includethose disclosed in U.S. Pat. No. 5,427,614, which is incorporated hereinby reference.

[0169] In one embodiment, the thermal-reversible carrier for making thecore or the shell, or a portion thereof, by solvent-free molding isselected from polyalkylene glycols, polyalkaline oxides, andcombinations thereof. In one particular such embodiment, the core orshell or portion thereof further comprises shellac as a strengtheningadjuvant. Advantageously, shellac may be employed as a strengtheningagent in the molded core or shell or portions thereof at a level fromabout 5 to about 15 weight percent of the molded portion, withoutimparting pH-dependency to the dissolution of the molded portion.

[0170] Suitable release-modifying moldable excipients for making thecore, or a portion thereof, by solvent-free or sovent based moldinginclude but are not limited to swellable erodible hydrophilic materials,pH-dependent polymers, pore formers, and insoluble edible materials.

[0171] In embodiments of the present invention wherein the shell isprepared by a solvent-free or solvent-based molding process, suitablerelease-modifying excipients are preferably selected from swellableerodible hydrophilic materials, pH dependent polymers, and insolubleedible materials.

[0172] Suitable swellable erodible hydrophilic materials for use asrelease-modifying excipients for making the core, or the shell, or aportion thereof by a solvent-free molding process include waterswellable cellulose derivatives, polyalkalene glycols, thermoplasticpolyalkalene oxides, acrylic polymers, hydrocolloids, clays, gellingstarches, and swelling cross-linked polymers, and derivitives,copolymers, and combinations thereof. Examples of suitable waterswellable cellulose derivatives include sodium carboxymethylcellulose,cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples ofsuitable polyalkalene glyclols include polyethylene glycol. Examples ofsuitable thermoplastic polyalkalene oxides include poly (ethyleneoxide). Examples of suitable acrylic polymers include potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL(high-molceular weight cross-linked acrylic acid homopolymers andcopolymers), and the like. Examples of suitable hydrocolloids includealginates, agar, guar gum, locust bean gum, kappa carrageenan, iotacarrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellangum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan,chitin, cyclodextrin, chitosan. Examples of suitable clays includesmectites such as bentonite, kaolin, and laponite; magnesiumtrisilicate, magnesium aluminum silicate, and the like, and derivativesand mixtures thereof. Examples of suitable gelling starches include acidhydrolyzed starches, swelling starches such as sodium starch glycolate,and derivatives thereof. Examples of suitable swelling cross-linkedpolymers include cross-linked polyvinyl pyrrolidone, cross-linked agar,and cross-linked carboxymethylcellose sodium.

[0173] Suitable pH-dependent polymers for use as release-modifyingmoldable excipients for making the molded matrix or molded core ormolded shell or a portion thereof by molding include enteric cellulosederivatives, for example hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, cellulose acetatephthalate; natural resins such as shellac and zein; enteric acetatederivatives such as for example polyvinylacetate phthalate, celluloseacetate phthalate, acetaldehyde dimethylcellulose acetate; and entericacrylate derivatives such as for example polymethacrylate-based polymerssuch as poly(methacrylic acid, methyl methacrylate) 1:2, which iscommercially available from Rohm Pharma GmbH under the tradenameEUDRAGIT S and poly(methacrylic acid, methyl methacrylate) 1:1, which iscommercially available from Rohm Pharma GmbH under the tradenameEUDRAGIT L and the like, and derivatives, salts, copolymers, andcombinations thereof.

[0174] Suitable pore formers for use as release-modifying excipients formaking the molded matrix, the core, the shell, or a portion thereof bymolding include water-soluble organic and inorganic materials. Examplesof suitable water-soluble organic materials include water solublepolymers including water soluble cellulose derivatives such ashydroxypropylmethylcellulose, and hydroxypropylcellulose; water solublecarbohydrates such as sugars, and starches; water soluble polymers suchas polyvinylpyrrolidone and polyethylene glycol, and insoluble swellingpolymers such as microcrystalline cellulose. Examples of suitable watersoluble inorganic materials include salts such as sodium chloride andpotassium chloride and the like and/or mixtures thereof.

[0175] Suitable insoluble edible materials for use as release-modifyingmoldable excipients for making the core, or the shell, or a portionthereof, by molding, include water-insoluble polymers, and low-meltinghydrophobic materials. Examples of suitable water-insoluble polymersinclude ethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers; and the like and derivatives,copolymers, and combinations thereof. Suitable low-melting hydrophobicmaterials include fats, fatty acid esters, phospholipids, and waxes.Examples of suitable fats include hydrogenated vegetable oils such asfor example cocoa butter, hydrogenated palm kernel oil, hydrogenatedcottonseed oil, hydrogenated sunflower oil, and hydrogenated soybeanoil; and free fatty acids and their salts. Examples of suitable fattyacid esters include sucrose fatty acid esters, mono, di, andtriglycerides, glyceryl behenate, glyceryl palmitostearate, glycerylmonostearate, glyceryl tristearate, glyceryl trilaurylate, glycerylmyristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoylmacrogol-32 glycerides. Examples of suitable phospholipids includephosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, andphosphotidic acid. Examples of suitable waxes include carnauba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystallinewax, and paraffin wax; fat-containing mixtures such as chocolate; andthe like.

[0176] In a preferred embodiment, the shell of the present invention,whether prepared by a solvent-free molding process, or by asolvent-based molding process, is substantially free of pores having adiameter of 0.5-5.0 microns. As used herein, “substantially free” meansthat the shell has a pore volume of less than about 0.02 cc/g,preferably less than about 0.01 cc/g, more preferably less than about0.005 cc/g in the pore diameter range of 0.5 to 5.0 microns. Incontrast, typical compressed materials have pore volumes of more thanabout 0.02 cc/g in this diameter range.

[0177] The pore volume, pore diameter and density of the shells used inthis invention may be determined using a Quantachrome InstrumentsPoreMaster 60 mercury intrusion porosimeter and associated computersoftware program known as “Porowin.” The procedure is documented in theQuantachrome Instruments PoreMaster Operation Manual. The PoreMasterdetermines both pore volume and pore diameter of a solid or powder byforced intrusion of a non-wetting liquid (mercury), which involvesevacuation of the sample in a sample cell (penetrometer), filling thecell with mercury to surround the sample with mercury, applying pressureto the sample cell by: (i) compressed air (up to 50 psi maximum); and(ii) a hydraulic (oil) pressure generator (up to 60000 psi maximum).Intruded volume is measured by a change in the capacitance as mercurymoves from outside the sample into its pores under applied pressure. Thecorresponding pore size diameter (d) at which the intrusion takes placeis calculated directly from the so-called “Washburn Equation”:d=−(4γ(cos θ))/P where γ is the surface tension of liquid mercury, θ isthe contact angle between mercury and the sample surface and P is theapplied pressure.

[0178] Equipment used for pore volume measurements:

[0179] (1) Quantachrome Instruments PoreMaster 60.

[0180] (2) Analytical Balance capable of weighing to 0.0001 g.

[0181] (3) Desiccator.

[0182] Reagents used for measurements:

[0183] (1) High purity nitrogen.

[0184] (2) Triply distilled mercury.

[0185] (3) High pressure fluid (Dila AX, available from Shell ChemicalCo.).

[0186] (4) Liquid nitrogen (for Hg vapor cold trap).

[0187] (5) Isopropanol or methanol for cleaning sample cells.

[0188] (6) Liquid detergent for cell cleaning.

[0189] Procedure:

[0190] The samples remain in sealed packages or as received in thedessicator until analysis. The vacuum pump is switched on, the mercuryvapor cold trap is filled with liquid nitrogen, the compressed gassupply is regulated at 55 psi., and the instrument is turned on andallowed a warm up time of at least 30 minutes. The empty penetrometercell is assembled as described in the instrument manual and its weightis recorded. The cell is installed in the low pressure station and“evacuation and fill only” is selected from the analysis menu, and thefollowing settings are employed:

[0191] Fine Evacuation time: 1 min.

[0192] Fine Evacuation rate: 10

[0193] Coarse Evacuation time: 5 min.

[0194] The cell (filled with mercury) is then removed and weighed. Thecell is then emptied into the mercury reservoir, and two tablets fromeach sample are placed in the cell and the cell is reassembled. Theweight of the cell and sample are then recorded. The cell is theninstalled in the low-pressure station, the low-pressure option isselected from the menu, and the following parameters are set:

[0195] Mode: Low pressure

[0196] Fine evacuation rate: 10

[0197] Fine evacuation until: 2001 μHg

[0198] Coarse evacuation time: 10 min.

[0199] Fill pressure: Contact+0.1

[0200] Maximum pressure: 50

[0201] Direction: Intrusion And Extrusion

[0202] Repeat: 0

[0203] Mercury contact angle; 140

[0204] Mercury surface tension: 480

[0205] Data acquisition is then begun. The pressure vs. cumulativevolume-intruded plot is displayed on the screen. After low-pressureanalysis is complete, the cell is removed from the low-pressure stationand reweighed. The space above the mercury is filled with hydraulic oil,and the cell is assembled and installed in the high-pressure cavity. Thefollowing settings are used:

[0206] Mode: Fixed rate

[0207] Motor speed: 5

[0208] Start pressure: 20

[0209] End pressure: 60,000

[0210] Direction: Intrusion and extrusion

[0211] Repeat: 0

[0212] Oil fill length: 5

[0213] Mercury contact angle: 140

[0214] Mercury surface tension: 480

[0215] Data acquisition is then begun and graphic plot pressure vs.intruded volume is displayed on the screen. After the high pressure runis complete, the low-and high-pressure data files of the same sample aremerged.

[0216] The shell of the present invention, whether prepared by asolvent-free molding process, or by a solvent-based molding process,typically has a surface gloss of at least about 150 gloss units, e.g. atleast about 175 gloss units, or at least about 190 gloss units, whenmeasured according to the method set forth in Example 6 herein. Incontrast, typical sprayed coatings have gloss values of less than about150 gloss units.

[0217] Dosage forms with high surface gloss are preferred by consumersdue to their aesthetic elegance and perceived swallowability. Thesurface gloss of the shell depends upon a number of factors, includingthe shell composition, the method of forming the shell, and, if a moldis used, the surface finish on the mold.

[0218] Shells of this invention may be tested for surface gloss using aninstrument available from TriCor Systems Inc. (Elgin, Ill.) under thetradename TRI-COR MODEL 805A/806H SURFACE ANALYSIS SYSTEM and generallyin accordance with the procedure described in “TriCor Systems WGLOSS 3.4Model 805A/806H Surface Analysis System Reference Manual” (1996), whichis incorporated by reference herein, except as modified below.

[0219] This instrument utilizes a CCD camera detector, employs a flatdiffuse light source, compares samples to a reference standard, anddetermines average gloss values at a 60 degree incident angle. Duringits operation, the instrument generates a gray-scale image, wherein theoccurrence of brighter pixels indicates the presence of more gloss atthat given location.

[0220] The instrument also incorporates software that utilizes agrouping method to quantify gloss, i.e., pixels with similar brightnessare grouped together for averaging purposes.

[0221] The “percent full scale” or “percent ideal” setting (alsoreferred to as the “percent sample group” setting), is specified by theuser to designate the portion of the brightest pixels above thethreshold that will be considered as one group and averaged within thatgroup. “Threshold,” as used herein, is defined as the maximum glossvalue that will not be included in the average gloss value calculation.Thus, the background, or the non-glossy areas of a sample are excludedfrom the average gloss value calculations. The method disclosed in K.Fegley and C. Vesey, “The Effect of Tablet Shape on the Perception ofHigh Gloss Film Coating Systems,” which is available at www.colorcon.comas of 18 Mar. 2002 and incorporated by reference herein, is used tominimize the effects resulting from different shell shapes, and toreport a metric that is comparable across the industry. (The 50% samplegroup setting is selected as the setting which best approximatesanalogous data from surface roughness measurements.)

[0222] After initially calibrating the instrument using a calibrationreference plate (190-228; 294 degree standard; no mask, rotation 0,depth 0), a standard surface gloss measurement may be created usinggel-coated caplets available from McNeil-PPC, Inc. under the tradenameExtra Strength TYLENOL Gelcaps. The average gloss value for a sample ofsuch gel-coated caplets may be determined, while employing the 25 mmfull view mask (190-280), and configuring the instrument to thefollowing settings:

[0223] Rotation: 0

[0224] Depth: 0.25 inches

[0225] Gloss Threshold: 95

[0226] % Full Scale: 50%

[0227] Index of Refraction: 1.57

[0228] The average surface gloss value for the reference standard isthen determined.

[0229] Each shell sample may then be independently tested in accordancewith the same procedure.

[0230] The weight of the shell is preferably about 10 to about 400% ofthe weight of the core. In embodiments wherein the shell is prepared bya solvent-free molding process, the weight of the shell is typicallyfrom about 50 to about 400%, e.g. from about 75 to about 400%, or about100 to about 200% percent of the weight of the core. In embodimentswherein the shell is prepared by a solvent-based molding process, theweight of the shell is typically from about 10 to about 100 percent,preferably from about 10 to about 60 percent of the weight of the core.

[0231] The shell provides a delay of greater than one hour, for exampleat least about 3 hours, or at least about 4 hours, or at least about 6hours, or at least about 12 hours to the onset of dissolution of theactive ingredient upon contacting of the dosage form with a liquidmedium such as water, gastrointestinal fluid or the like. The delayperiod is typically controlled by the shell thickness, composition, or acombination thereof. In one embodiment the delay period is independentof the pH of the dissolution media or fluid environment. For example,the average lag-time for dissolution of active ingredient in 0.1 N HClis not substantially different (i.e. within about 30 minutes, preferablywithin about 15 minutes) from the average lag-time for the dissolutionof active ingredient in pH 5.6 buffer system.

[0232] Typical shell thicknesses which may be employed in this inventionare about 50 to about 4000 microns. In embodiments wherein the shell isprepared by a solvent-free molding process, the shell typically has athickness of about 500 to about 4000 microns, e.g. about 500 to about2000 microns, say about 800 to about 1200 microns. In embodimentswherein the shell is prepared by a solvent-based molding process, theshell typically has a thickness of less than about 800 microns, e.g.about 100 to about 600 microns, say about 150 to about 400 microns.

[0233] In one embodiment of the invention, the shell additionallycomprises at least one active ingredient which may be the same ordifferent than the active ingredient contained in the core.

[0234] In another embodiment of this invention, at least one activeingredient contained within the dosage form exhibits a delayed burstrelease profile. By “delayed burst release profile” it is meant that therelease of that particular active ingredient from the dosage form isdelayed for a pre-determined time after ingestion by the patient, andthe delay period (“lag time”) is followed by prompt (immediate) releaseof that active ingredient. The shell of the present invention providesfor the delay period and is preferaby substantially free of the activeingredient to be released in a delayed burst manner. In suchembodiments, the delayed burst active ingredient is typically containedwithin the core or a portion thereof. In these embodiments, the core maybe prepared by compression or molding, and is formulated for immediaterelease, as is known in the art, so that the core is readily solubleupon contact with the dissolution medium. In such embodiments the corepreferably comprises a disintegrant, and optionally comprises additionalexcipients such as fillers or thermoplastic materials selected fromwater-soluble or low-melting materials, and surfactants or wettingagents. In these embodiments, the dissolution of the burst releaseactive ingredient, after the delay period, meets USP specifications forimmediate release tablets containing that active ingredient. Forexample, for acetaminophen tablets, USP 24 specifies that in pH 5.8phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least80% of the acetaminophen contained in the dosage form is releasedtherefrom within 30 minutes after dosing, and for ibuprofen tablets, USP24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2(paddles) at 50 rpm, at least 80% of the ibuprofen contained in thedosage form is released therefrom within 60 minutes after dosing. SeeUSP 24, 2000 Version, 19-20 and 856 (1999).

[0235] In another embodiment of this invention at least one activeingredient contained within the dosage form exhibits a delayed andsustained release profile. By “delayed then sustained release profile”it is meant that the release of that particular active ingredient fromthe dosage form is delayed for a pre-determined time after ingestion bythe patient, and the delay period (“lag time”) is followed by sustained(prolonged, extended, or retarded) release of that active ingredient.The shell of the present invention provides for the delay period, and ispreferraby substantially free of the active to be released in a delayedthen sustained manner. In such embodiments, the delayed then sustainedrelease active ingredient is preferrably contained within the core. Insuch embodiments the core may function for example as an eroding matrixor a diffusional matrix, or an osmotic pump. In embodiments in which thecore or a portion thereof functions as a diffusional matrix throughwhich active ingredient is liberated in a sustained, extended,prolonged, or retarded manner, the core portion preferably comprises arelease-modifying excipient selected from combinations of insolubleedible materials and pore-formers. Alternately, in such embodiments inwhich the core portion is prepared by molding, the thermal-reversiblecarrier may function by dissolving and forming pores or channels throughwhich the active ingredient may be liberated. In embodiments in whichthe core or a portion thereof functions as an eroding matrix from whichdispersed active ingredient is liberated in a sustained, extended,prolonged, or retarded manner, the core portion preferably comprises arelease-modifying compressible or moldable excipient selected fromswellable erodible hydrophilic materials, pH-dependent polymers, andcombinations thereof.

[0236] In one embodiment, the shell is not a compression coating appliedto the core.

[0237] This invention will be illustrated by the following examples,which are not meant to limit the invention in any way.

EXAMPLE 1

[0238] Dosage forms according to the invention, comprising a core withina shell, were prepared as follows.

[0239] The following ingredients were used to make the shells: TABLE AWeight Mg/ Shell Trade Name Manufacturer percent Tablet PolyethyleneCarbowax ® Union Carbide 45.0 250 Glycol 3350 Corporation, Danbury, CTPolyethylene Polyox ® Union Carbide 15.0 83 Oxide WSR N-80 Corporation,(MW 200,000) Danbury, CT Shellac Powder Regular Mantrose-Haeuser 20.0111 bleached Company, shellac Atteboro, MA Triethyl Citrate Morflex,Inc., 10.0 56 Greensboro, NC Croscarmellose Ac-Di-Sol ® FMC Corporation,10.0 56 Sodium Newark, DE

[0240] The shell material was prepared as follows: a beaker wassubmersed in a 70° C. water bath (Ret digi-visc; Antal-Direct, Wayne,Pa.). Polyethylene glycol (PEG) 3350 was added to the beaker and wasmixed with a spatula until all PEG was melted. Shellac powder, which wasscreened through 40-mesh screen, was added to the molten PEG and wasmixed until all powder was dispersed. Triethyl citrate was added to themolten PEG and was mixed for 1 minute. Polyethylene oxide (PEO)(MW=200,000) was added and was mixed for 10 minutes. Croscarmellosesodium was added and was mixed for 2 minutes. The shell material wasprovided in flowable form.

[0241] The following commercially available product was used as thecore: TABLE B Weight Tablet Trade Name Manufacturer percent Mg/TabletPseudoephedrine Nasal CVS Pharmacy, 23.0 165 HCL core tabletdecongestant Inc., Woonsocket, tablet 30 mg RI

[0242] The shell was molded according to the following process: alaboratory scale (round, tablet-shaped, 0.4375″ diameter) stainlesssteel mold assembly was used to apply the shells to the cores. The moldassembly comprised a lower mold portion and an upper mold portion, withno temperature control. 350 to 450 mg of the molten shell material wasintroduced into the mold cavity formed by the lower mold portion. Apseudoephedrine HCL core tablet (Table B) was then inserted into themold cavity. Additional molten shell material was added to fill the moldcavity and the upper mold portion was manually applied to form a moldedtablet. After 10 seconds, the upper mold portion was removed, and themolded dosage form was ejected from the lower mold portion.

EXAMPLE 2

[0243] Dosage forms according to the invention, comprising a core withina shell, were prepared as follows.

[0244] The following ingredients were used to make the shells: TABLE CTrade Weight Mg/ Shell Name Manufacturer percent Tablet LauroylMacrogol-32 Gelucire Gattefosse Corp., 70.0 751 Glycerides 50/13Westwood, NJ Lauroyl Macrogol-32 Gelucire Gattefosse Corp., 30.0 322Glycerides 44/14 Westwood, NJ

[0245] The shell material was prepared in the following manner: a beakerwas submersed in a water bath (Ret digi-visc; Antal-Direct, Wayne, Pa.)where the water temperature was set at 70° C. Lauroyl Macrogol-32glycerides were added to the beaker and were mixed with a spatula untilall the glycerides were melted. The shell material was provided inflowable form.

[0246] The shell material was applied to the cores of Example 1, usingthe laboratory scale mold assembly of Example 1, in the followingmanner: 700 to 800 mg of the molten shell material (Table C) wasintroduced into the mold cavity formed by the lower mold portion. Apseudoephedrine HCL core tablet (Example 1) was then inserted into themold cavity. Additional molten mixture was added to fill the mold cavityand the upper mold portion was manually applied to form a molded tablet.After 10 seconds, the upper mold portion was removed, and the moldeddosage form was ejected from the lower mold portion.

EXAMPLE 3

[0247] Dosage forms according to the invention, comprising a core withina shell, were prepared as follows.

[0248] The following ingredients were used to make the shells: TABLE DWeight Mg/ Shell Trade Name Manufacturer percent Tablet PolyethyleneCarbowax ® Union Carbide 65.0 430 Glycol 3350 Corporation, Danbury, CTHydroxypropyl Methocel Dow Chemical 25.0 165 Methylcellulose K4M PermCo., Midland, CR MI Hydroxpropylcellulose Klucel Hercules 10.0 66 EXAFIncorporated, Pharm Wilmington, DE

[0249] The shell material was prepared in the following manner: a beakerwas submersed in a water bath (Ret digi-visc; Antal-Direct, Wayne, Pa.)where the water temperature was set at 70° C. PEG 3350 was added to thebeaker and was mixed with a spatula until all PEG was melted.Hydroxypropyl methylcellulose and hydroxpropylcellulose were added tothe molten PEG and mixed for 10 minutes. The shell material was providedin flowable form.

[0250] The following ingredients were used to make the cores: TABLE EWeight Mg/ Granulation Trade Name Manufacturer percent Tablet IbuprofenAlbemarle Corp., 93.24 200 Orangeburg, SC Sodium Starch ExplotabMendell, A Penwest 5.59 12 Glycolate Co., Patterson, NY ColloidalSilicon Cab-O-Sil Cabot Corp., 0.23 0.5 Dioxide Tuscola, IL MagnesiumMallinckrodt Inc., 0.93 2 Stearate St. Louis, MO

[0251] The cores were made in the following manner: Ibuprofen wasscreened through a #20 mesh screen and was added to a plastic bag.Sodium starch glycolate was screened through a #30 mesh screen and wasadded to the plastic bag. The powder was blended by manual shaking for 2minutes. Half of the powder was removed from the first plastic bag andwas added to a second plastic bag containing colloidal silicon dioxideand magnesium stearate. The powder in the second bag was then blended bymanual shaking for 1 minute and was passed a #20 mesh screen. Theresultant powder blend was added to the first bag and further blended bymanual shaking for 1 minute. The blend was then compressed into tabletsusing a Manesty Beta-press (Thomas Engineering, Inc., Hoffman Estates,Ill.) fitted with round, concave punch and die unit having 0.3125″diameter.

[0252] The shell material was applied to the cores, using a laboratoryscale metal mold assembly (0.5065″, round), made from a lower moldassembly portion comprising a lower mold cavity, and an upper moldassembly portion comprising an upper mold cavity. The dosage form wasprepared in the following manner 400 to 450 mg of the molten shellmaterial (Table D) was introduced into the lower mold cavity formed bythe lower mold assembly. An ibuprofen core tablet as described above wasthen inserted into the lower mold cavity. Additional molten shellmaterial was then introduced into the upper mold cavity formed by theupper mold assembly. The upper mold assembly was mated with the lowermold assembly to form a dosage form. After 60 seconds, the upper andlower mold assemblies were separated, and the dosage form was removedfrom the mold.

EXAMPLE 4

[0253] The release profiles for the active ingredients contained in thedosage forms of Examples 1-3 were compared with those of the same activeingredients from other dosage forms. Results are shown in FIGS. 2-4.

[0254] All dissolution testing was performed according to the followingmethod:

[0255] Apparatus: USP Type I apparatus (Basket, 100 RPM).

[0256] Media: 0.1 N HCL and pH 5.6 phosphate buffer at 37° C. The pH ofthe buffer was switched from 0.1N HCL to pH 5.6 phosphate buffer at the2 hour time point.

[0257] Time points: Samples were tested at 0.5, 1, 2, 3, 4, 6, and 8hours for pseudoephedrine HCL.

[0258] Analysis: Dissolution samples were analyzed for pseudoephedrineHCL versus a standard prepared at the theoretical concentration for 100percent released of each compound. Samples were analyzed using a HPLCequipped with a Waters® 717 Autoinjector and a Waters® 486 UV detectorset at a wavelength of 214 nm. The mobile phase was prepared using 55percent acetonitrile and 45 percent 18 mM Potassium phosphate buffer.The injection volume was 50 μL with a run time of approximately 8minutes and a pump flow of 2.0 mL/min. The column used was a Zorbax®300-SCX (4.6 mm×25 cm).

[0259]FIG. 2 depicts the percent release of active ingredient(pseudoephedrine HCL) vs. time (hours) for the dosage form of Example 1,as well as the percent release of pseudoephedrine vs. time (hours) for acommercially available immediate release dosage form (Nasal decongestanttablet made by CVS Pharmacy, Inc.— Table B). Curve (a) shows the releaseof pseudoephedrine HCl from the dosage form of Example 1. Curve (b)shows the release of pseudoephedrine HCl from the immediate releasecomparitor tablet. As shown in FIG. 2, the dosage form of Example 1exhibited a delay of about 3 hours to the onset of release of activeingredient.

[0260]FIG. 3 depicts the percent release of active ingredient(pseudoephedrine HCL) vs. time (hours) from the dosage form of Example2, as well as the percent release of pseudoephedrine vs. time (hours)from a commercially available immediate release tablet (Sudafed®). Asshown in FIG. 3, the dosage form of Example 2 exhibited a delay of about4 hours to the onset of release of active ingredient. Curve (a) showsthe release rate of pseudoephedrine HCL of this invention. Curve (d) wasderived from the commercially immediate release dosage forms of Sudafed®tablet (containing pseudoephedrine HCL).

[0261]FIG. 4 depicts the percent release of active ingredient(Ibuprofen) vs. time (hours) for the dosage form of Example 3. As shownin FIG. 4, the dosage form of Example 3 exhibited a delay of about 8hours to the onset of release of active ingredient.

EXAMPLE 5

[0262] Dosage forms according to the invention, comprising a compressedcore within a molded shell, are made in a continuous process using anapparatus comprising a compression module and a thermal cycle moldingmodule linked in series via a transfer device as described at pages14-16 of copending U.S. application Ser. No. 09/966,939, the disclosureof which is incorporated herein by reference. The shells are made of ashell flowable material comprising the ingredients shown in Table Dabove and prepared in flowable form as described in Example 3. The coresare made of the ingredients shown in Table E above and prepared as apowder as described in Example 3. The cores are first compressed on acompression module as described in copending U.S. application Ser. No.09/966,509 at pages 16-27. The compression module is a double row,rotary apparatus, comprising a fill zone, insertion zone, compressionzone, ejection zone, and purge zone as shown in FIG. 6 of U.S.application Ser. No. 09/966,509. The dies of the compression module arefilled using vacuum assistance, with mesh screen filters located in diewall ports of each die.

[0263] The cores are transferred from the compression module to thethermal cycle molding module via a transfer device. The transfer devicehas the structure shown as 300 in FIG. 3 and described on pages 51-57 ofcopending U.S. application Ser. No. 09/966,414, the disclosure of whichis incorporated by reference. It comprises a plurality of transfer units304 attached in cantilever fashion to a belt 312 as shown in FIGS. 68and 69. The transfer device rotates and operates in sync with thecompression and thermal cycle molding modules to which it is coupled.Transfer units 304 comprise retainers 330 for holding the cores as theytravel around the transfer device.

[0264] The thermal cycle molding module has the general configurationshown in FIG. 3 and pages 27-51 of copending U.S. application Ser. No.09/966,497, which depicts a thermal cycle molding module 200 comprisinga rotor 202 around which a plurality of mold units 204 are disposed. Thethermal cycle molding module includes reservoir 206 (see FIG. 4) forholding the shell flowable material. In addition, the thermal cyclemolding module is provided with a temperature control system for rapidlyheating and cooling the mold units. FIGS. 55 and 56 of pending U.S.application Ser. No. 09/966,497 depict the temperature control system600.

[0265] The thermal cycle molding module is of the type shown in FIG. 28Aof copending U.S. application Ser. No. 09/966,497. The mold units 204 ofthe thermal cycle molding module comprise upper mold assemblies 214,rotatable center mold assemblies 212 and lower mold assemblies 210 asshown in FIG. 28C. Cores are continuously transferred to the moldassemblies, which then close over the cores.

[0266] Coating is performed in two steps, first and second portions ofthe shell portions being applied separately as shown in the flow diagramof FIG. 28B of copending U.S. application Ser. No. 09/966,497. In afirst step, a first portion of shell flowable material, heated to aflowable state in reservoir 206, is injected into the mold cavitiescreated by the closed mold assemblies. The temperature of the firstportion is then decreased, hardening it over half the core. The moldassemblies separate, the center mold assembly rotates, and then the moldassemblies again close. In a second step, the second portion of theshell flowable material, heated to a flowable state in reservoir 206, isinjected into the mold cavities. The temperature of the second portionis then decreased, hardening it over the other half of the core. Themold assemblies separate, and the finished dosage forms are ejected fromthe apparatus.

[0267] Although this invention has been illustrated by reference tospecific embodiments, it will be apparent to those skilled in the artthat various changes and modifications may be made which clearly fallwithin the scope of this invention.

The invention claimed is:
 1. A dosage form comprising: (a) a corecomprising at least one active ingredient; and (b) a molded shell whichsurrounds the core, wherein the shell provides a predetermined timedelay of greater than one hour for the onset of dissolution of theactive ingredient upon contacting of the dosage form with a liquidmedium and the delay is independent of the pH of the liquid medium. 2.The dosage form of claim 1, in which the shell comprises means fordelaying the onset of dissolution of the active ingredient for greaterthan one hour upon contacting of the dosage form with a liquid medium,and the delay is independent of the pH of the liquid medium.
 3. Thedosage form of claim 1, wherein the weight of the shell is at least 50percent of the weight of the core.
 4. The dosage form of claim 1,wherein the shell has a thickness from about 500 to about 4000 microns.5. The dosage form of claim 1, wherein the shell has a thickness fromabout 100 to 600 microns.
 6. The dosage form of claim 1, wherein theshell is substantially free of pores having a diameter of 0.5 to 5.0microns.
 7. The dosage form of claim 1, wherein the shell comprises atleast about 30% of a thermal reversible carrier.
 8. The dosage form ofclaim 1, wherein the shell comprises at least about 10% of afilm-former.
 9. The dosage form of claim 1, in which the shelladditionally comprises at least one active ingredient which may be thesame or different than the active ingredient contained in the core. 10.The dosage form of claim 1, which additionally comprises an outercoating which covers at least a portion of the shell, and the outercoating comprises at least one active ingredient which may be the sameor different than the active ingredient contained in the core.
 11. Thedosage form of claim 1, in which the core is a compressed tablet. 12.The dosage form of claim 1, in which the core comprises coated particlesof at least one active ingredient.
 13. The dosage form of claim 1, inwhich the core is prepared by molding.
 14. The dosage form of claim 1,in which the core is substantially free of pores having a diameter of0.5 to 5.0 microns.
 15. The dosage form of claim 1, in which the corecomprises at least about 30 weight percent of a thermal-reversiblecarrier.
 16. The dosage form of claim 1, in which the core comprises arelease-modifying excipient.
 17. The dosage form of claim 1, in whichthe shell is not a compression coating applied to the core.
 18. Thedosage form of claim 1, which provides an immediate release of at leastone active ingredient, followed by a delay of at least about 1 hour,followed by a burst release of at least one active ingredient.
 19. Thedosage form of claim 1, wherein the shell is prepared using asolvent-free molding process.
 20. The dosage form of claim 1, whereinthe shell comprises at least 30% by weight of a thermal-reversiblecarrier.
 21. The dosage form of claim 1, wherein the shell comprises upto 55% by weight of a swellable, erodible hydrophilic material.
 22. Thedosage form of claim 1, wherein the shell is prepared using asolvent-based molding process.
 23. The dosage form of claim 1, whereinthe shell comprises at least 10% by weight of a film-former.
 24. Thedosage form of claim 1, wherein the shell comprises at least 55% byweight of a release-modifying excipient.
 25. The dosage form of claim 1,wherein the dosage form comprises means for providing a delayed burstrelease profile of the active ingredient.
 26. The dosage form of claim1, wherein the dosage form comprises means for providing a delayed andsustained release profile of the active ingredient.
 27. The dosage formof claim 1, wherein the dosage form comprises means for providing apulsatile release profile of the active ingredient.
 28. The dosage formof claim 1, wherein the core or portion thereof further comprisesshellac at a level of about 5 to about 15 weight percent of the core orportion thereof.
 29. The dosage form of claim 1, wherein the shell orportion thereof further comprises shellac at a level of about 5 to about15 weight percent of the shell or portion thereof.
 30. The dosage formof claim 20, wherein the thermal reversible carrier is selected from thegroup consisting of polyethylene glycol, polyethylene oxide andcopolymers and combinations thereof.
 31. The dosage form of claim 23,wherein the film former is polyethylene oxide.
 32. The dosage form ofclaim 24, wherein the release-modifying excipient is a swellingcross-linked polymer.
 33. The dosage form of claim 32, wherein theswelling cross-linked polymer is croscarmellose sodium.
 34. The dosageform of claim 1, wherein the shell further comprises a plasticizer. 35.The dosage form of claim 34, wherein the plasticizer is tributylcitrate.
 36. The dosage form of claim 22, wherein the weight of theshell is from about 10 percent to about 60 percent of the weight of thecore.